US3488419A - Oral compositions for calculus retardation - Google Patents
Oral compositions for calculus retardation Download PDFInfo
- Publication number
- US3488419A US3488419A US731312A US3488419DA US3488419A US 3488419 A US3488419 A US 3488419A US 731312 A US731312 A US 731312A US 3488419D A US3488419D A US 3488419DA US 3488419 A US3488419 A US 3488419A
- Authority
- US
- United States
- Prior art keywords
- acid
- ethane
- salt
- hydroxy
- calculus
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title description 91
- 239000002253 acid Substances 0.000 description 59
- 150000003839 salts Chemical class 0.000 description 57
- -1 phenylethenyl Chemical group 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 21
- 210000003298 dental enamel Anatomy 0.000 description 18
- 239000000606 toothpaste Substances 0.000 description 18
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 17
- 229940034610 toothpaste Drugs 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 14
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 13
- 229910052791 calcium Inorganic materials 0.000 description 13
- 239000011575 calcium Substances 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000002324 mouth wash Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
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- 239000013078 crystal Substances 0.000 description 9
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- 206010044029 Tooth deposit Diseases 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 8
- 208000006558 Dental Calculus Diseases 0.000 description 7
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 7
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- 229910052736 halogen Inorganic materials 0.000 description 6
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- RHWUIRMVPYNGIV-UHFFFAOYSA-N 1,3,4-triphosphonobutan-2-ylphosphonic acid Chemical compound OP(O)(=O)CC(P(O)(O)=O)C(P(O)(O)=O)CP(O)(O)=O RHWUIRMVPYNGIV-UHFFFAOYSA-N 0.000 description 4
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
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- CCSPRGDNSSMNIH-UHFFFAOYSA-N 1,2,4,5,6-pentaphosphonohexan-3-ylphosphonic acid Chemical compound OP(O)(=O)CC(P(O)(O)=O)C(P(O)(O)=O)C(P(O)(O)=O)C(P(O)(O)=O)CP(O)(O)=O CCSPRGDNSSMNIH-UHFFFAOYSA-N 0.000 description 3
- SFRLSTJPMFGBDP-UHFFFAOYSA-N 1,2-diphosphonoethylphosphonic acid Chemical compound OP(O)(=O)CC(P(O)(O)=O)P(O)(O)=O SFRLSTJPMFGBDP-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- FRCICXIVPRNPLM-UHFFFAOYSA-N [amino(phosphono)methyl]phosphonic acid Chemical compound OP(=O)(O)C(N)P(O)(O)=O FRCICXIVPRNPLM-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 230000002272 anti-calculus Effects 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
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- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical compound OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000000979 retarding effect Effects 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-O triethanolammonium Chemical class OCC[NH+](CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-O 0.000 description 3
- ZWVMLYRJXORSEP-LURJTMIESA-N (2s)-hexane-1,2,6-triol Chemical compound OCCCC[C@H](O)CO ZWVMLYRJXORSEP-LURJTMIESA-N 0.000 description 2
- UWOPXOPPISBKGY-UHFFFAOYSA-N 1,2,4,5-tetraphosphonopentan-3-ylphosphonic acid Chemical compound OP(O)(=O)CC(P(O)(O)=O)C(P(O)(O)=O)C(P(O)(O)=O)CP(O)(O)=O UWOPXOPPISBKGY-UHFFFAOYSA-N 0.000 description 2
- SXGRAKNNKBAFML-UHFFFAOYSA-N 1,3-diphosphonopropan-2-ylphosphonic acid Chemical compound OP(O)(=O)CC(P(O)(O)=O)CP(O)(O)=O SXGRAKNNKBAFML-UHFFFAOYSA-N 0.000 description 2
- ROPQINLWRARCTM-UHFFFAOYSA-N 2-phosphonopropan-2-ylphosphonic acid Chemical compound OP(=O)(O)C(C)(C)P(O)(O)=O ROPQINLWRARCTM-UHFFFAOYSA-N 0.000 description 2
- RBJBFHZUIPIEJX-UHFFFAOYSA-N 5-phosphonononan-5-ylphosphonic acid Chemical compound CCCCC(P(O)(O)=O)(P(O)(O)=O)CCCC RBJBFHZUIPIEJX-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
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- 235000013162 Cocos nucifera Nutrition 0.000 description 2
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229920000877 Melamine resin Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ZYNHDFDXWSKMCD-UHFFFAOYSA-N [acetamido(phosphono)methyl]phosphonic acid Chemical compound CC(=O)NC(P(O)(O)=O)P(O)(O)=O ZYNHDFDXWSKMCD-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
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- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 229920003090 carboxymethyl hydroxyethyl cellulose Polymers 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000010634 clove oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 230000002328 demineralizing effect Effects 0.000 description 1
- 210000004268 dentin Anatomy 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- IVJISJACKSSFGE-UHFFFAOYSA-N formaldehyde;1,3,5-triazine-2,4,6-triamine Chemical class O=C.NC1=NC(N)=NC(N)=N1 IVJISJACKSSFGE-UHFFFAOYSA-N 0.000 description 1
- HANVTCGOAROXMV-UHFFFAOYSA-N formaldehyde;1,3,5-triazine-2,4,6-triamine;urea Chemical class O=C.NC(N)=O.NC1=NC(N)=NC(N)=N1 HANVTCGOAROXMV-UHFFFAOYSA-N 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 210000004195 gingiva Anatomy 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- JWSMTBMIGYJJJM-UHFFFAOYSA-N magnesium;azane Chemical compound N.[Mg+2] JWSMTBMIGYJJJM-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000007974 melamines Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 235000019960 monoglycerides of fatty acid Nutrition 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 239000012875 nonionic emulsifier Substances 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007788 roughening Methods 0.000 description 1
- 210000001581 salivary duct Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000019983 sodium metaphosphate Nutrition 0.000 description 1
- UGJCNRLBGKEGEH-UHFFFAOYSA-N sodium-binding benzofuran isophthalate Chemical compound COC1=CC=2C=C(C=3C(=CC(=CC=3)C(O)=O)C(O)=O)OC=2C=C1N(CCOCC1)CCOCCOCCN1C(C(=CC=1C=2)OC)=CC=1OC=2C1=CC=C(C(O)=O)C=C1C(O)=O UGJCNRLBGKEGEH-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000271 synthetic detergent Substances 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229920001187 thermosetting polymer Polymers 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3839—Polyphosphonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/55—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F5/00—Softening water; Preventing scale; Adding scale preventatives or scale removers to water, e.g. adding sequestering agents
- C02F5/08—Treatment of water with complexing chemicals or other solubilising agents for softening, scale prevention or scale removal, e.g. adding sequestering agents
- C02F5/10—Treatment of water with complexing chemicals or other solubilising agents for softening, scale prevention or scale removal, e.g. adding sequestering agents using organic substances
- C02F5/14—Treatment of water with complexing chemicals or other solubilising agents for softening, scale prevention or scale removal, e.g. adding sequestering agents using organic substances containing phosphorus
Definitions
- compositions which term is used herein to designate products which in the ordinary course of usage are retained in the oral cavity for a time sufficient to contact substantially all of the dental surfaces, but are not intentionally ingested.
- Such products include, for example, dentifrices, mouthwashes, prophylaxis pastes and topical solutions.
- Dental calculus or tartar as it is sometimes called, is a deposit which forms on the surfaces of the teeth at the gingival margin. Supraginival calculus appears principally in the areas near the orifices of the salivary ducts; e.g., on the lingual surfaces of the lower anterior teeth and on the buccal surfaces of the upper first and second molars, and on the distal surfaces of the posterior molars.
- Mature calculus consists of an inorganic portion which is largely calcium phosphate arranged in a hydroxylapatite crystal lattice structure similar to bone, enamel and dentine.
- An organic portion is also present and consists of desquamated epithelial cells, leukocytes, salivary sediment, food debris and various types of microorganisms.
- the mature calculus As the mature calculus develops, it becomes visibly white or yellowish in color unless stained or discolored by some extraneous agency. In addition to being unsightly and undesirable from an aesthetic standpoint, the mature calculus deposits are constant sources of irritation of the gingiva and thereby are a contributing factor to gingivitis and other diseases of the supporting structures of the teeth, the irritation decreasing the resistance of tissues to endogeneous and exogenous organisms.
- polyphosphonates possess the surprising capacity to retard the development of dental calculus without removing calcium from dental enamel or otherwise damaging the tooth structure when employed in oral compositions maintained within defined pH limits.
- Operable polyphosphonates for use in the compositions of this invention are characterized in that their molecular structure contains at least two geminal or three vicinal phosphono groups. Although these compounds may possess only nominal calcium sequestering capacities in the pH range characteristic of oral compositions, they effectively retard calculus formation by a mechanism that is believed to involve the inhibition of hydlroxylapatite crystal growth as will be discussed more fully hereinafter.
- the polyphosphonates employed in the compositions of this invention resist hydrolysis in aqueous products and therefore remain in an active form throughout the normal shelf-life or such products.
- R and R are hydrogen or CH OH; n is an integer of from 3 to 10; R is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, aryl (e.g., phenyl and naphthyl), phenylethenyl, benzyl, halogen (e.g., chlorine bromine, and fluorine), amino, substituted amino (e.g., di-
- (OH) or -CH CH(PO H R is hydrogen, lower alkyl (e.g., methyl, ethyl, propyl, and butyl), amino, benzyl, halogen (e.g., chlorine, bromine and fluorine), hydI'OXYl, CH PO H or or a pharmaceutically acceptable salt thereof such as alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., calcium and magnesium), and ammonium or low molecular weight substituted ammonium (e.g., mono-, di-, and triethanolammonium) salts, and a carrier suitable for use in the oral cavity, the pH of the composition being within the range from about 5.0 to about 11.0.
- alkali metal e.g., sodium and potassium
- alkaline earth metal e.g., calcium and magnesium
- ammonium or low molecular weight substituted ammonium e.g., mono-, di-, and triethanolammonium
- Operable polyphosphonates of the above Formula I include propane-1,2,3-triphosphonic acid; butane-1,2,3,4-tetraphosphonic acid; hexane-1,2,3,4,5,6-hexaphosphonic acid; hexane-l-hydroxy-2,3 ,4,5,6-pentaphosphonic acid; hexane-1,6-dihydroxy-2,3,4,5-tetraphosphonic acid; pentane-1,2,3,4,5-pentaphosphonic acid; heptane-l,2,3,4,5,6,7-heptaphosphonic acid; octane-1,2,3,4,5,6,7,8-octaphosphonic acid; non'ane-1,2,3,4,5,6,7,8,9-nonaphosphonic acid; decane-l,2,3,4,5,6,7,8,9,10-decaphosphonic acid;
- salts of these acids e.g., sodium, potassium, calcium, magnesium, ammonium, triethanolammonium, diethanolammonium, and monoethanolammoniurn salts.
- operable polyphosphonates encompassed by the above Formula II are ethane-l-hydroxy-l ,l-diphosphonic acid; methanediphosphonic acid; methanehydroxydiphosphonic acid; ethane-1,1,2-triphosphonic acid; propane-1,1,3 ,3-tetraphosphonic acid; ethane-2-phenyl-1,l-diphosphonic acid; ethane-Z-naphthyl-l,l-diphosphonic acid; methanephenyldiphosphonic acid; ethane-1-amino-l,l-diphosphonic acid; methanedichlorodiphosphonic acid; nonane-5,5-diphosphonic acid; n-pentane-1,1-diphosphonic acid; methanedifiuorodiphosphonic acid; methanedibromodiphosphonic acid; propane-2,2-diphosphonic acid; ethane-2-carboxy-1,
- salts of these acids e.g., sodium, potassium, calcium, magnesium ammonium, triethanolammonium, diethanolammonium and monoethanolammonium salts.
- Ethane-l-hydroxy-l,l-diphosphonic acid an especially preferred polyphosphonate, has the molecular formula CH C(OH) (PO H (According to nomenclature by radicals, the acid might also be named l-hydroxyethylidene diphosphonic acid.)
- the most readily crystallizable salt of this acid is obtained when three of the acid hydrogens are replaced by sodium.
- Preferred salts for the purpose of this invention are the trisodium hydrogen salt which has the structure:
- the trisodium hydrogen salt normally crystallizes as the hexahydrate which loses some water during air-drying to yield a mixture of the hexaand monohydrate averag ing 3 to 4 molecules of water of hydration.
- any pharmaceutically acceptable salt of ethane-lhydroxy-1,1-diphosphonic acid can be used in the practice of this invention, the tetrasodium salt, the trisodium hydrogen salt, the disodium dihydrogen salt, the monosodium trihydrogen salt, the monocalcium salt and the mixtures thereof preferred.
- the other pharmaceutically acceptable salts and mixtures thereof are also suitable.
- These compounds can be prepared by any suitable method, however, an especially preferred method is disclosed in copending application Ser. No. 553,648, filed May 31, 1966, by Oscar T. Quimby et al., now Patent No. 3,400,149.
- Methanehydroxydiphosphonic acid and related compounds operable herein can be prepared, for example, by reaction of phosgene with an alkali metal dialkyl phosphite.
- a complete description of these compounds and the method for preparing same is found in copending patent application Ser. No. 517,073, filed Dec. 29, 1965, by Oscar T. Quimby, now Patent No. 3,422,137.
- Mcthancdiphosphonic acid and related compounds useful herein are described in detail in US. Patent 3,213,030, granted Oct. 19, 1965.
- a preferred method of preparing such compounds is disclosed in copending application Ser. No. 218,862, filed Aug. 23, 1962, by Clarence H. Roy, now Patent No. 3,251,907.
- Ethane-1,1,,2-triphosphonic acid and related compounds which can be used in the compositions of this invention as Well as a method for their preparation are fully described in copending patent application Ser. No. 602,161, filed Dec. 16, 1966, by Oscar T. Quimby.
- Pentane-2,2-diphosphonic acid and related compounds can be prepared in accordance with the method described Kosolopoif in J. Amer. Chem. Soc., 75, 1500 Propane-1,2,3-triphosphonic acid and salts thereof can be prepared by a process disclosed in the commonly assigned copending application of D. Allan Nicholson and Darrel Campbell, Ser. No. 694,002, filed Dec. 27, 1 967.
- Butane-1,2,3,4-tetraphosphonic acid and salts thereof can be prepared by a process disclosed in the commonly assigned copending application of D. Allan Nicholson and Darrel Campbell, Ser. No. 694,003, filed Dec. 27, 1967.
- the higher aliphatic vicinal polyphosphonates and salts thereof can be prepared by the process disclosed in the commonly assigned copending application of D. Allan Nicholson and Darrel Campbell, Ser. No. 693,898, filed Dec. 27, 1967.
- the concentration of polyphosphonate in the oral compositions of this invention can range from about .0l% to about by weight. Oral compositions which in the ordinary course of usage could be accidentally ingested should contain lower concentrations of polyphosphonate. Thus, a mouthwash in accordance with this invention preferably contains less than about 3% by weight of polyphosphonate. Dentifrice compositions, topical solutions and prophylaxis pastes, the latter to be administered professionally, can contain up to about 10% by weight, preferably from about 0.1% to about 5.0% by weight of polyphosphonate.
- the pH of the composition of this invention can range from about 5.0 to about 11. Below about pH 5.0 damage to the dental enamel can occur in spite of the relative safety of the polyphosphonates. Above about pH 11.0 difiiculty is encountered in formulating products having satisfactory flavor and mildness. A preferred pH range is from about 7.0 to about 10.
- the pH of the composition is determinative of the predominant salt form of the polyphosphonates present therein. For example, at pH 7.0 ethane-l-hydroxy-l, l-diphosphonate is predominantly in the disodium form.
- Rat calculus study Two groups of to 21-day-old Holtzman-Sprague- Dawley strain rats, each group comprising one male and one female member of each of 10 liters, were employed in this test, one group serving as the control and the other serving as the test group. Both groups of animals were placed on a calculus inducing diet consisting of 63 cornstarch, 32% non-fat dry milk, 2% liver powder and 3% celluflour. Topical applications of a 0.5% aqueous solution of trisodium hydrogen ethane-l-hydroxy-l,l-diphosphonate adjusted to pH 10.0 were made on the teeth of each of the animals in the test group for about one minute twice daily, five days per week for three weeks. Similar applications of water were made to each animal in the control group during the experimental period.
- 1 ml. of a 0.1 M stock solution of NaH PO 'H O is diluted with 22 ml. of distilled water.
- 1 ml. of an aqueous solution of the polyphosphonate to be tested (at a concentration sufficient to provide the desired ultimate concentration in the reaction mixture) is added to the diluted NaH PO solution and the solution is adjusted to pH 7.4 with sodium hydroxide.
- To this solution is added 1 ml. of a 0.1 M solution of CaCl -2H O preadjusted to pH 7.4 with sodium hydroxide. This mixture is held at a constant pH 7.4 throughout the reaction period.
- the solution is filtered through a 0.45,c Millipore filter pad.
- the precipitate is air-dried and analyzed by X-ray diffraction.
- the solid calcium phosphate precipitated from the abovedescribed solution without a polyphosphonate gives a typical hydroxylapatite pattern, while the calcium phosphate precipitated under the-same conditions but in the presence of small amounts of the polyphosphonates of this invention is amorphous to X-rays.
- Table 3 below shows the concentration of various polyphosphonates tested required to inhibit the formation of calcium hydroxylapatite under the conditions specified above.
- the safety of polyphosphonates for use in contact with dental surfaces is determined by the Continuous Immersion Test conducted as follows: Mature human teeth are immersed in aqueous solutions or dispersions of oral compositions containing polyphosphonate in accordance with this invention at pH 7.0 and pH 10. Every four hours the teeth are examined for decalcification. Under visible light, enamel decalcification can be detected by a loss of luster, white opaque spots or slight surface roughening. The teeth are examined macroscopically and microscopically at the end of seven days. If no decalcification is observed through this period, the compositions cause no damage to dental enamel, and are considered safe in this respect for use in the oral cavity.
- the safety of polyphosphonates for use in contact with dental enamel can also be established by measuring the amount of phosphate released from a given area of dental enamel in the course of a standard exposure to an aqueous solution of the polyphosphonate as fully described by Tucker et al. in US. Patent 3,175,951, granted Mar. 30, 1965.
- Toothpaste compositions conventionally contain abrasive materials, sudsing agents, binders, humectants, flavoring and sweetening agents.
- the abrasive materials and other adjuncts used in the practice of this invention are preferably not sources of much soluble calcium so that the crystal growth inhibiting capacity of polyphosphonate is not depleted to an extent that its anticalculus activity is impaired.
- conventional abrasives such as dicalcium orthophosphate and calcium carbonate are preferably not used.
- predominantly B-phase calcium pyrophosphate prepared in accordance with the teachings of Schweizer, US. Patent 3,112,247, granted Nov. 26, 1963, which contains relatively little soluble calcium can be used.
- An especially preferred class of abrasives for use herein are the particulate thermosetting polymerized resins as described by Cooley et al. in US. Patent 3,070,510, granted Dec. 25, 1962.
- Suitable resins include, for example, melamines, phenolics, ureas, melamine-ureas, melamine-formaldehydes, urea-formaldehydes, melamine urea formaldehydes, cross-linked epoxides, and cross-linked polyesters.
- Suitable abrasives include alumina and the in soluble non-calcium metaphosphates such as sodium metaphosphate. Mixtures of abrasives can also be used.
- the total amount of abrasive in the dentifrice embodiments of this invention can range from 0.5% to 95% by weight of the dentifrice.
- toothpastes contain from 20% to 60% by weight of abrasive.
- Abrasive particle size preferably ranges from 2 1 to 20 Suitable sudsing agents are those which are reasonably stable and form suds throughout a wide pH range, preferably non-soap anionic organic synthetic detergents.
- Such agents are water-soluble salts of alkyl sulfate having from to 18 carbon atoms in the alkyl radical, such as sodium lauryl sulfate; water-soluble salts of sulfonated monoglycerides of fatty acids having from 10 to 18 carbon atoms, such as sodium monoglyceride sulfonates; salts of C C fatty acid amides of taurine, such as sodium N-methyl-N-palmitoyl taurine; salts of C C fatty acid esters of isethionic acid; and substantially saturated aliphatic acyl amides of saturated monoaminocarboxylfc acids having 2 to 6 carbon atoms and in which the acyl radical contains 12 to 16 carbon atoms, such as sodium N-lauroyl sarcoside. Mixtures of two or more sudsing agents can be used.
- the sudsing agent can be present in the dentifrice compositions of this invention in an amount from 0.5% to 5% by weight of the total compositions.
- thickening agents are hydroxyethyl cellulose and water-soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose.
- Natural gums such as gum karaya, gum arabic, and gum tragacanth can also be used.
- Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve texture.
- Thickening agents in an amount from 0.5% to 5.0% by weight of the total composition can be used.
- humectant material in a toothpaste to keep it from hardening.
- Suitable humectants include glycerine, sorbitol, and other edible polyhydric alcohols.
- the humectant can comprise up to about 36% by weight of the toothpaste composition.
- Suitable flavoring agents include oil of Wintergreen, oil of peppermint, oil of spearmint, oil of sassafras, and oil of clove.
- sweetening agents which can be used include saccharin, dextrose, levulose and sodium cyclamate.
- Example I A toothpaste of the following composition was prepared by conventional methods:
- Toothpaste compositions substantially identical to the composition of Example I are prepared with the trisodium salt of methanediphosphonic acid; the disodium salt of methane-hydroxydiphosphonic acid; ethane-l-amino-l, 1- diphosphonic acid; trisodium salt of methanedichlorodiphosphonic acid; and propane-2, 2-diphosphonic acid, respectively, rather than the disodium salt of ethane-1- hydroxy-l, l-diphosphonic acid, adjusting the pH to 5.9.
- These compositions substantially retard calculus formation and do not decalcify dental enamel.
- Example II A toothpaste was prepared which was substantially identical in composition to the toothpaste of Example I except that 3.0 parts rather than 1.5 parts of disodium dihydrogen ethane-l-hydroxy-l, l-disphosphonate and 30.08 parts rather than 31.58 parts of water was used. This composition was also found to be effective and caused no damage to dental enamel after seven days exposure.
- the disodium dihydrogen salt of ethane-l-hydroxy-l, l-diphosphonic acid in the above composition can be replaced by ethane-l-hydroxy-l, l-diphosphonic acid, or any of the potassium, ammonium, or substituted ammonium salts thereof, adjusting the pH of the composition to 7.0, and substantially equivalent results are attained.
- Example III Yet another toothpaste was prepared having the following composition:
- this toothpaste retards the formation of dental calculus and no decalcification of dental enamel was observed after seven days exposure.
- Example IV A toothpaste composition prepared with 3.0 parts of disodium dihydrogen ethane-l-hydroxy-l, l-diphosph onate and 38.08 parts water, but otherwise substantially identical to the composition of Example III, was prepared. This composition was found to be effective against calculus formation and caused no observable decalcification of dental enamel after seven days exposure.
- the disodium dihydrogen salt of ethane-1-hydroxy-1,ldiphosphonic acid employed in this example can be replaced with dipotassium dihydrogen ethane-1-hydroxy-1,1- diphosphonate; diammonium dihydrogen ethane-l-hydroxy-1,1-diphosphonate; or bis(triethanolamrnonium)dihydrogen ethane-l-hydroxy-l,l-diphosphonate, respectively, adjusting the pH of the composition to 8.0. Substantially equivalent results are obtained with these compositions.
- Example V 1 Polyoxyethylene (20 moles of ethylene oxide) sorbitan monooleatea nonionic emulsifier supplied by Atlas Powder Company.
- each of the above compositions materially reduces accumulation of calculus on the surfaces of teeth. No decalcification was observed after seven days exposure of dental enamel to these compositions.
- Mouthwash compositions corresponding to Example VII are prepared, substituting the dirnagnesium salt of propane-1,1,3,3-tetraphosphonic acid; the disodium salt of propane-,Z-diphosphonic acid; the tetraammonium salt of ethane-2-carboxy-1,l-diphosphonic acid; nonane-5,5-diphosphonic acid; n-pentane-l,l-diphosphonic acid and ethane-Z-phenyl-l,l-diphosphonic acid, respectively, for the disodium salt of ethane-l-hydroxy-l,l-diphosphonic acid and adjusting the pH to 10.0.
- These mouthwash compositions retard calculus formation without damaging tooth structure.
- Mouthwash compositions corresponding to Example V are prepared, replacing the disodium salt of ethane-l-hydroxy-1,1-diphosphonic acid with pent-4-ene-1-hydroxy- 1,1-diphosphonic acid; octadec-9-enel-hydroxy- 1, l-diphosphonic acid; methane-dichlorodiphosphonic acid; methanedibromodiphosphonic acid; phenylaminoethanediphosphonic, respectively.
- Each of the resulting mouthwash compositions retard calculus formation without damaging dental enamel.
- a number of additional mouthwash compositions are prepared which are similar in formulation to the composition of Example VIII but replacing the disodium salt of ethane-l-hydroxy-l,1-diph0sphonic acid with the disodium salt of hexane-1-hydroxy-2,3,4,5,6-pentaphosphonic acid, the triammonium salt of hexane-1,6-dihydroxy-2,3,4,5 tetraphosphonic acid, the dicalcium salt of pentane- 1,2,3,4,5-pentaphosphonic acid, heptane-l,2,3,4,5,6,7-heptaphosphonic acid and octane-1,2,3,4,5,6,7,8-octa.phosphonic acid, respectively.
- These compositions are effective in retarding dental calculus formation without damaging dental enamel.
- Example IX A prophylaxis paste for use by the dentist for removal of stains and polishing the teeth after mechanical removal of calculus deposits is formulated as follows:
- the prophylaxis paste set forth above is modified by replacing the trisodium salt of ethane-l-hydroxydiphosphonic acid with N,N-dimethylaminoethanediphosphonic acid; N (2 hydroxyethyl) aminomethanediphosphonic acid; N-acetylaminomethanediphosphonic acid; and aminomethanediphosphonic acid, respectively, with comparable results.
- dodecane-l,l-diphosphonic acid the dipotassium salt of 3-phenyl-1,l-diphosphonoprop-Z-ene, or the dimagnesium salt of decane-1,2,3,4,5,6,7,8,9,10-decaphosphonic acid can be used in place of the trisodium salt of ethane-l-hydroxy-1,1-diphosphonic aicd in the composition of Example IX with good results.
- Toothpowders and the like can be prepared by conventional methods and containing, in addition to the usual ingredients, an amount of polyhphosphonate within the ranges specified herein, to provide an effective means of retarding calculus formation without damaging the tooth structure.
- An oral composition effective in inhibiting the formation of dental calculus without adversely affecting tooth structure comprising (1) from about .01% to about 10% by weight of a polyphosphonate selected from the group consisting of those of the formulae:
- R and R are each hydrogen or CH OI-I; n is an integer of from 3 to 10; R is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, phenyl, naphthyl, phenylethyl, benzyl, halogen, amino, dimethylamino, diethylamino, N-hydroxy-N-ethylamino, acetylamino,
- R is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl CH COOH, CH PO H or CH CH PO H or a pharmaceutically acceptable salt thereof, and (2) a carrier suitable for use in the oral cavity, the pH of the composition being within the range from about 5.0 to about 11.0.
- composition of claim 1 in which the polyphosphonate is ethane-1-hydroxy-1,l-diphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is methanediphosphonic acid or a pharmaceutical-ly acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is ethane-l-hydroxy-l,1,2-triphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is methanehydroxydiphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polypho-sphonate is propane-1,1,3,3-tetraphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is ethane-Z-carboxy-l,l-diphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is ethane-1,1,2-triphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is ethane-1-amino-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is nonane-5,S-diphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 13 in which the polyphosphonate is n-pentane-l,l-diphosphonic acid or a pharmecutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is methanedibromodiphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is pronane-l-hydroxy-1,3-triphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is propane-1,2,3-triphosphor1ic acid or a pharmaoeutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is butane-1,2,3,4-tetraphosphonic acid or a pharmaceutically acceptable salt thereof.
- composition of claim 1 in which the polyphosphonate is hexane-1,2,3,4,5,6-hexaphosphonic acid or a pharmaceutically acceptable salt thereof.
- a toothpaste composition comprising (1) from about 0.1% to about 5.0% by weight of a polyphosphonate selected from the group consisting of those of the formulae:
- R and R are each hydrogen or CH OH; n is an integer of from 3 to 10; R is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino, dimethylamino, diethylamino, N-hydroxy-N-ethylamino, acety-lamino,
- R is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl, CH COOH, CH PO H or CH OH PO H or a pharmaceutical-1y acceptable salt thereof, and (2) from about 20% to about 60% by weight of an abrasive material, the pH of said composition being within the range from about 7 to about 10.
- composition of claim 19 in which the polyphosphonate is ethane-l-hydroxy-l,l-diphosphonic acid or a pharmaceutically acceptable salt thereof.
Description
3,488,419 ORAL COMPOSETIONS FOR CALCULUS RETARDATION Homer W. McCune, Wyoming, and Nathaniel B. Tucker, Glendale, Ohio, assignors to The Procter & Gamble Company, Cincinnati, Ohio, a corporation of Ohio No Drawing. Continuation-impart of application Ser. No. 693,713, Dec. 27, 1967, which is a continuation-in-part of application Ser. No. 668,702, Sept. 18, 1967, which, in turn, is a continuation-in-part of application Ser. No. 512,548, Dec. 8, 1965. This application May 22, 1968, Ser. No. 731,312
Int. Cl. A61k 7/16 US. Cl. 424-49 20 Claims ABSTRACT OF THE DISCLOSURE Oral compositions, such as toothpaste, mouthwash, and the like, containing certain polyphosphonic acids and their salts which retard dental calculus formation without damaging tooth structure.
Cross-reference to related applications This application is a continuation-in-part of the copending application of Homer W. McCune and Nathaniel B. Tucker, Ser. No. 693,713, filed Dec. 27, 1967, which 15 a continuation-in-part of copending application Ser. No. 668,702, filed Sept. 18, 1967, which in turn is a continuation-in-part of copending application Ser. No. 512,- 548, filed Dec. 8, 1965, all now abandoned.
Background of the invention The field of this invention is oral compositions which term is used herein to designate products which in the ordinary course of usage are retained in the oral cavity for a time sufficient to contact substantially all of the dental surfaces, but are not intentionally ingested. Such products include, for example, dentifrices, mouthwashes, prophylaxis pastes and topical solutions.
Dental calculus, or tartar as it is sometimes called, is a deposit which forms on the surfaces of the teeth at the gingival margin. Supraginival calculus appears principally in the areas near the orifices of the salivary ducts; e.g., on the lingual surfaces of the lower anterior teeth and on the buccal surfaces of the upper first and second molars, and on the distal surfaces of the posterior molars.
Mature calculus consists of an inorganic portion which is largely calcium phosphate arranged in a hydroxylapatite crystal lattice structure similar to bone, enamel and dentine. An organic portion is also present and consists of desquamated epithelial cells, leukocytes, salivary sediment, food debris and various types of microorganisms.
As the mature calculus develops, it becomes visibly white or yellowish in color unless stained or discolored by some extraneous agency. In addition to being unsightly and undesirable from an aesthetic standpoint, the mature calculus deposits are constant sources of irritation of the gingiva and thereby are a contributing factor to gingivitis and other diseases of the supporting structures of the teeth, the irritation decreasing the resistance of tissues to endogeneous and exogenous organisms.
A wide variety of chemical and biological agents have been suggested in the art to retard calculus formation or to remove calculus after it is formed. Mechanical removal of this material periodically by the dentist is, of course, routine dental office procedure.
The chemical approach to calculus inhibition generally involves chelation of calcium ion which prevents the calculus from forming and/or breaks down mature cal- United States Patent "ice culus by removing calcium. A number of chelating agents have been employed for this purpose. See, for example, British Patent 490,384, granted Feb. 15, 1937, which discloses oral compositions containing ethylenediaminetetraacetic acid, nitrilotriacetic acid and related compounds as antic'alculus agents; German Auslegeschrift 1,149,138, published May 22, 1963, which discloses certainwater-soluble diglycolates as anticalculus agents; and US. Patent 1,516,206 which discloses oral compositions containing various sugar lactones for this purpose.
Although certainof the art-disclosed chelators are purportedly safe for use on dental enamel, the chemical similarity of calculus to the tooth structure limits the usefulness of the chelation approach since the more effective chelators can seriously damage the tooth structure by decalcification. Thus, the development of oral compositions which effectively retard calculus by calcium chelation has been impeded by safety considerations.
Summary of the invention It has now been discovered that certain polyphosphonic acids and salts thereof (referred to collectively hereinafter as polyphosphonates) possess the surprising capacity to retard the development of dental calculus without removing calcium from dental enamel or otherwise damaging the tooth structure when employed in oral compositions maintained within defined pH limits.
Operable polyphosphonates for use in the compositions of this invention are characterized in that their molecular structure contains at least two geminal or three vicinal phosphono groups. Although these compounds may possess only nominal calcium sequestering capacities in the pH range characteristic of oral compositions, they effectively retard calculus formation by a mechanism that is believed to involve the inhibition of hydlroxylapatite crystal growth as will be discussed more fully hereinafter.
Unlike inorganic polyphosphates such as pyrophosphates, the polyphosphonates employed in the compositions of this invention resist hydrolysis in aqueous products and therefore remain in an active form throughout the normal shelf-life or such products.
It is therefore an object of this invention to provide novel oral compositions which retard the formation of calculus without otherwise affecting the tooth structure.
It is another object of this invention to provide an improved method for retarding the development of dental calculus.
Other objects will become apparent from the following detailed description.
phonate selected from the group consisting of those of the formulae:
wherein R and R are hydrogen or CH OH; n is an integer of from 3 to 10; R is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, aryl (e.g., phenyl and naphthyl), phenylethenyl, benzyl, halogen (e.g., chlorine bromine, and fluorine), amino, substituted amino (e.g., di-
(OH) or -CH CH(PO H R is hydrogen, lower alkyl (e.g., methyl, ethyl, propyl, and butyl), amino, benzyl, halogen (e.g., chlorine, bromine and fluorine), hydI'OXYl, CH PO H or or a pharmaceutically acceptable salt thereof such as alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., calcium and magnesium), and ammonium or low molecular weight substituted ammonium (e.g., mono-, di-, and triethanolammonium) salts, and a carrier suitable for use in the oral cavity, the pH of the composition being within the range from about 5.0 to about 11.0.
Operable polyphosphonates of the above Formula I include propane-1,2,3-triphosphonic acid; butane-1,2,3,4-tetraphosphonic acid; hexane-1,2,3,4,5,6-hexaphosphonic acid; hexane-l-hydroxy-2,3 ,4,5,6-pentaphosphonic acid; hexane-1,6-dihydroxy-2,3,4,5-tetraphosphonic acid; pentane-1,2,3,4,5-pentaphosphonic acid; heptane-l,2,3,4,5,6,7-heptaphosphonic acid; octane-1,2,3,4,5,6,7,8-octaphosphonic acid; non'ane-1,2,3,4,5,6,7,8,9-nonaphosphonic acid; decane-l,2,3,4,5,6,7,8,9,10-decaphosphonic acid;
and the pharmaceutically acceptable salts of these acids, e.g., sodium, potassium, calcium, magnesium, ammonium, triethanolammonium, diethanolammonium, and monoethanolammoniurn salts.
Among the operable polyphosphonates encompassed by the above Formula II are ethane-l-hydroxy-l ,l-diphosphonic acid; methanediphosphonic acid; methanehydroxydiphosphonic acid; ethane-1,1,2-triphosphonic acid; propane-1,1,3 ,3-tetraphosphonic acid; ethane-2-phenyl-1,l-diphosphonic acid; ethane-Z-naphthyl-l,l-diphosphonic acid; methanephenyldiphosphonic acid; ethane-1-amino-l,l-diphosphonic acid; methanedichlorodiphosphonic acid; nonane-5,5-diphosphonic acid; n-pentane-1,1-diphosphonic acid; methanedifiuorodiphosphonic acid; methanedibromodiphosphonic acid; propane-2,2-diphosphonic acid; ethane-2-carboxy-1,
l-diphosphonic acid; propane-1-hydroxy-1,1,3 -triphosphonic acid; ethane-Z-hydroxy-1,1,2-triphosphonic acid; ethane- 1 -hydroxy-1 1 ,2-triphosphonic acid; propane-1,3-diphenyl-2,2-diphosphonic acid; nonane-1,1-diphosphonic acid; hexadecane-1,1-diphosphonic acid; pent-4-ene-1-hydroxy-1,l-diphosphonic acid; octadec-9-ene-l-hydroxy-1,1'diphosphonic acid; 3-phenyl-1,1-diphosphonoprop-2-ene; octane-1,1-diphosphonic acid; dodecane-1,1-disphosphonic acid; phenylaminomethanediphosphonic acid; naphthylaminomethanediphosphonic acid; -N,N-dimethylaminomethanediphosphonic acid; N-(Z-hydroxyethyl)-aminomethanediphosphonic acid; N-acetylaminomethanediphosphonic acid; aminomethanediphosphonic acid;
and the pharmaceutically acceptable salts of these acids, e.g., sodium, potassium, calcium, magnesium ammonium, triethanolammonium, diethanolammonium and monoethanolammonium salts.
Mixtures of any of the foregoing phosphonic acids and/ or salts can be used in the compositions of this invention.
Ethane-l-hydroxy-l,l-diphosphonic acid, an especially preferred polyphosphonate, has the molecular formula CH C(OH) (PO H (According to nomenclature by radicals, the acid might also be named l-hydroxyethylidene diphosphonic acid.) The most readily crystallizable salt of this acid is obtained when three of the acid hydrogens are replaced by sodium. Preferred salts for the purpose of this invention are the trisodium hydrogen salt which has the structure:
P O; CH3--OH] 3Na+ P0 11 and the disodium salt. 1
The trisodium hydrogen salt normally crystallizes as the hexahydrate which loses some water during air-drying to yield a mixture of the hexaand monohydrate averag ing 3 to 4 molecules of water of hydration.
While any pharmaceutically acceptable salt of ethane-lhydroxy-1,1-diphosphonic acid can be used in the practice of this invention, the tetrasodium salt, the trisodium hydrogen salt, the disodium dihydrogen salt, the monosodium trihydrogen salt, the monocalcium salt and the mixtures thereof preferred. The other pharmaceutically acceptable salts and mixtures thereof are also suitable. These compounds can be prepared by any suitable method, however, an especially preferred method is disclosed in copending application Ser. No. 553,648, filed May 31, 1966, by Oscar T. Quimby et al., now Patent No. 3,400,149.
Methanehydroxydiphosphonic acid and related compounds operable herein can be prepared, for example, by reaction of phosgene with an alkali metal dialkyl phosphite. A complete description of these compounds and the method for preparing same is found in copending patent application Ser. No. 517,073, filed Dec. 29, 1965, by Oscar T. Quimby, now Patent No. 3,422,137.
Mcthancdiphosphonic acid and related compounds useful herein are described in detail in US. Patent 3,213,030, granted Oct. 19, 1965. A preferred method of preparing such compounds is disclosed in copending application Ser. No. 218,862, filed Aug. 23, 1962, by Clarence H. Roy, now Patent No. 3,251,907.
Ethane-1,1,,2-triphosphonic acid and related compounds which can be used in the compositions of this invention as Well as a method for their preparation are fully described in copending patent application Ser. No. 602,161, filed Dec. 16, 1966, by Oscar T. Quimby.
Propane-1,1,3,3-tetraphosphonic acid and related compounds useful herein, and a method for preparing same are fully disclosed in copending application Ser. No. 507,662, filed Nov. 15, 1965, by Oscar T. Quimby, now Patent No. 3,400,176.
Pentane-2,2-diphosphonic acid and related compounds can be prepared in accordance with the method described Kosolopoif in J. Amer. Chem. Soc., 75, 1500 Propane-1,2,3-triphosphonic acid and salts thereof can be prepared by a process disclosed in the commonly assigned copending application of D. Allan Nicholson and Darrel Campbell, Ser. No. 694,002, filed Dec. 27, 1 967.
Butane-1,2,3,4-tetraphosphonic acid and salts thereof can be prepared by a process disclosed in the commonly assigned copending application of D. Allan Nicholson and Darrel Campbell, Ser. No. 694,003, filed Dec. 27, 1967.
The higher aliphatic vicinal polyphosphonates and salts thereof can be prepared by the process disclosed in the commonly assigned copending application of D. Allan Nicholson and Darrel Campbell, Ser. No. 693,898, filed Dec. 27, 1967.
The concentration of polyphosphonate in the oral compositions of this invention can range from about .0l% to about by weight. Oral compositions which in the ordinary course of usage could be accidentally ingested should contain lower concentrations of polyphosphonate. Thus, a mouthwash in accordance with this invention preferably contains less than about 3% by weight of polyphosphonate. Dentifrice compositions, topical solutions and prophylaxis pastes, the latter to be administered professionally, can contain up to about 10% by weight, preferably from about 0.1% to about 5.0% by weight of polyphosphonate.
The pH of the composition of this invention can range from about 5.0 to about 11. Below about pH 5.0 damage to the dental enamel can occur in spite of the relative safety of the polyphosphonates. Above about pH 11.0 difiiculty is encountered in formulating products having satisfactory flavor and mildness. A preferred pH range is from about 7.0 to about 10. The pH of the composition, of course, is determinative of the predominant salt form of the polyphosphonates present therein. For example, at pH 7.0 ethane-l-hydroxy-l, l-diphosphonate is predominantly in the disodium form.
While it is not intended that this invention be limited by a particular theory of operation, it has been observed that the polyphosphonates encompassed herein interfere with the progress of calculus formation by interfering with the conversion of amorphous calcium phosphate to crystalline calcium hydroxylapatite. Amounts of polyphosphonates which are much too small to chelate any appreciable quantities of calcium have been found to retard the formation of calcium hydroxylapatite. This selective action on the formative calculus deposits without demineralizing action on the dental enamel is surprising.
The efiicacy of the compositions of this invention in calculus prophylaxis was demonstrated by the Rat Calculus and Crystal Growth Inhibition Tests which were conducted as follows:
Rat calculus study (topical) Two groups of to 21-day-old Holtzman-Sprague- Dawley strain rats, each group comprising one male and one female member of each of 10 liters, were employed in this test, one group serving as the control and the other serving as the test group. Both groups of animals were placed on a calculus inducing diet consisting of 63 cornstarch, 32% non-fat dry milk, 2% liver powder and 3% celluflour. Topical applications of a 0.5% aqueous solution of trisodium hydrogen ethane-l-hydroxy-l,l-diphosphonate adjusted to pH 10.0 were made on the teeth of each of the animals in the test group for about one minute twice daily, five days per week for three weeks. Similar applications of water were made to each animal in the control group during the experimental period.
Three weeks after the commencement of the test, the animals were sacrificed and their molars were graded for severity of calculus by assessing the area and depth of accumulation on each of the 44 dental surfaces examined in each animal. Grading was made on a 0-3 scale for each surface, 0 being no detectable calcified deposits, 3 being coverage of 50100% of the surface with a thick deposit and intermediate values representing gradations between these extremes. The total calculus score for each animal was determined by adding the grades for each of the 44 surfaces.
The results obtained in two such experiments are set forth in Table 1 below.
It can be seen that substantial reductions in calculus formation are attained with topically applied compositions in accordance with this invention.
Crystal growth inhibition determination As hereinbefore stated, the polyphosphonates inhibit the growth of calcium hydroxylapatite crystals and in this way interfere with the normal formation of calcium hydroxylapatite from solution. This test is to determine the effect of the polyphosphonates on the calcium phosphate formed on addition of calcium ion to orthophosphate ion at constant pH. The procedure is as follows:
1 ml. of a 0.1 M stock solution of NaH PO 'H O is diluted with 22 ml. of distilled water. 1 ml. of an aqueous solution of the polyphosphonate to be tested (at a concentration sufficient to provide the desired ultimate concentration in the reaction mixture) is added to the diluted NaH PO solution and the solution is adjusted to pH 7.4 with sodium hydroxide. To this solution is added 1 ml. of a 0.1 M solution of CaCl -2H O preadjusted to pH 7.4 with sodium hydroxide. This mixture is held at a constant pH 7.4 throughout the reaction period.
After a sufficient reaction time as determined by the operator, generally within minutes, the solution is filtered through a 0.45,c Millipore filter pad. The precipitate is air-dried and analyzed by X-ray diffraction. The solid calcium phosphate precipitated from the abovedescribed solution without a polyphosphonate gives a typical hydroxylapatite pattern, while the calcium phosphate precipitated under the-same conditions but in the presence of small amounts of the polyphosphonates of this invention is amorphous to X-rays.
Those compounds which were effective in inhibiting the growth of hydroxylapatite crystals at concentrations of less than l.5 10 in. under the conditions of this test were found to be effective in reducing calculus formation in rats, while several compounds outside the scope of this invention that had little or no effect in this test did not reduce calculus in rats.
Table 3 below shows the concentration of various polyphosphonates tested required to inhibit the formation of calcium hydroxylapatite under the conditions specified above.
TABLE 3 M Concentration Compound for Inhibition Ethane-l-hydroxy-l,l-diphosphonic acid, trisodium salt 2. 00 1O- Methane diphosphonic acid, trisodium salt 1. 82 10- Methanehydroxydiphosphonic acid, disodium salt. 2. 04 10- Ethane-1,1,Z-triphosphonic acid, tetrasodium salt. 2. 00X10- Propanel,1,3,3-tet1aphosphonic acid, hexasodium salt 1.16X10- Ethane-l-amiuo-l.l-diphosphonic acid 1. 00 10- Methanedichlorodiphosphonic acid, trisodium salt 2. 00 10- Nonane-5,5-diphosphonic acid 2. 00X10- n-Pentane-l,l-diphosphonic acid 2. 00x10 N 0nane-1,1-diph0spl1ouic acid. disodium salt. 2. 01 10 Mcthanedibromodiphosphonic acid 5. 04X10- Ethane-2-carboxy-l,l-diphosphonic acid, tctrasod um s 2. 26Xl0- Propanc-l-hydroxy-I,1,3-triphosphonic acid, pentasodium salt 1. 02Xl0- Ethane-l-hydroxy-l,1,2-triphosphonic acid, pentasodium salt 1. 1$ l0- Ethane-Z-hydroxy-1,1,2-triphosphonic acid, pentasodium salt 1. 05x10- Methaueaminodiphosphouic acid 2. 00 1O- Phenylaminornethanediphosphonic acid 2. 60X10- N.N-dimethylaminomethanediphosphonic acid. 5. 00Xl0- N-(Zhydroxyethyl) aminomethanediphosphonic acid 5. 20x10" N-ac0tylaminomethanediphosphonic acid 2. 22X10- Propane-1,2,3-triphosphonic acid 2. 32 10- Butane-1,2,3,4-tetraphosphonic acid 2. 04X1O- Hexane-1,2,3,4,5,6-hexaphosphouic acid 2. 22x1c 3'phenyl-l,l-diphosphonopropQ-ene, disodium sa 2. 04x10- The presence of the specified amounts of the polyphosphonates of Table 3 in the test solutions of the Crystal Growth Inhibition Test results in the precipitation of an amorphous calcium phosphate rather than crystalline calcium hydroxylapatite as occurs without polyphosponate and the total formation of calcium. orthophosphate is greatly decreased. By way of comparison, ethylenediaminetetraacetic acid and nitrilotriacetic acid which have been suggested for use as anticalculus agents in the art fail to inhibit crystal growth at molar concentrations of 2.45 10- and 2.54 lrespectively. At higher concentrations, these prior art compounds prevent precipitation of calcium phosphate in this test because of their power calcium sequestering properties.
The safety of polyphosphonates for use in contact with dental surfaces is determined by the Continuous Immersion Test conducted as follows: Mature human teeth are immersed in aqueous solutions or dispersions of oral compositions containing polyphosphonate in accordance with this invention at pH 7.0 and pH 10. Every four hours the teeth are examined for decalcification. Under visible light, enamel decalcification can be detected by a loss of luster, white opaque spots or slight surface roughening. The teeth are examined macroscopically and microscopically at the end of seven days. If no decalcification is observed through this period, the compositions cause no damage to dental enamel, and are considered safe in this respect for use in the oral cavity.
The safety of polyphosphonates for use in contact with dental enamel can also be established by measuring the amount of phosphate released from a given area of dental enamel in the course of a standard exposure to an aqueous solution of the polyphosphonate as fully described by Tucker et al. in US. Patent 3,175,951, granted Mar. 30, 1965.
A dentifrice, especially toothpaste, containing a polyphosphonate is a preferred embodiment of this invention. Toothpaste compositions conventionally contain abrasive materials, sudsing agents, binders, humectants, flavoring and sweetening agents.
The abrasive materials and other adjuncts used in the practice of this invention are preferably not sources of much soluble calcium so that the crystal growth inhibiting capacity of polyphosphonate is not depleted to an extent that its anticalculus activity is impaired. Thus, conventional abrasives such as dicalcium orthophosphate and calcium carbonate are preferably not used. However, predominantly B-phase calcium pyrophosphate prepared in accordance with the teachings of Schweizer, US. Patent 3,112,247, granted Nov. 26, 1963, which contains relatively little soluble calcium can be used. An especially preferred class of abrasives for use herein are the particulate thermosetting polymerized resins as described by Cooley et al. in US. Patent 3,070,510, granted Dec. 25, 1962. Suitable resins include, for example, melamines, phenolics, ureas, melamine-ureas, melamine-formaldehydes, urea-formaldehydes, melamine urea formaldehydes, cross-linked epoxides, and cross-linked polyesters.
Other suitable abrasives include alumina and the in soluble non-calcium metaphosphates such as sodium metaphosphate. Mixtures of abrasives can also be used. In any case, the total amount of abrasive in the dentifrice embodiments of this invention can range from 0.5% to 95% by weight of the dentifrice. Preferably, toothpastes contain from 20% to 60% by weight of abrasive. Abrasive particle size preferably ranges from 2 1 to 20 Suitable sudsing agents are those which are reasonably stable and form suds throughout a wide pH range, preferably non-soap anionic organic synthetic detergents. Examples of such agents are water-soluble salts of alkyl sulfate having from to 18 carbon atoms in the alkyl radical, such as sodium lauryl sulfate; water-soluble salts of sulfonated monoglycerides of fatty acids having from 10 to 18 carbon atoms, such as sodium monoglyceride sulfonates; salts of C C fatty acid amides of taurine, such as sodium N-methyl-N-palmitoyl taurine; salts of C C fatty acid esters of isethionic acid; and substantially saturated aliphatic acyl amides of saturated monoaminocarboxylfc acids having 2 to 6 carbon atoms and in which the acyl radical contains 12 to 16 carbon atoms, such as sodium N-lauroyl sarcoside. Mixtures of two or more sudsing agents can be used.
The sudsing agent can be present in the dentifrice compositions of this invention in an amount from 0.5% to 5% by weight of the total compositions.
In preparing toothpastes, it is necessary to add some thickening material to provide a desirable consistency. Preferred thickening agents are hydroxyethyl cellulose and water-soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as gum karaya, gum arabic, and gum tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve texture. Thickening agents in an amount from 0.5% to 5.0% by weight of the total composition can be used.
It is also desirable to include some humectant material in a toothpaste to keep it from hardening. Suitable humectants include glycerine, sorbitol, and other edible polyhydric alcohols. The humectant can comprise up to about 36% by weight of the toothpaste composition.
Suitable flavoring agents include oil of Wintergreen, oil of peppermint, oil of spearmint, oil of sassafras, and oil of clove. sweetening agents which can be used include saccharin, dextrose, levulose and sodium cyclamate.
Several representative oral compositions illustrating this invention are set forth in the following examples.
Example I A toothpaste of the following composition was prepared by conventional methods:
Parts by weight Water 31.58 Sorbitol 6.25 Saccharin 0.12 Calcium pyrophosphate 1 39.00 Glycerine 18.00 Sodium alkyl (coconut) sulfate 0.40 Sodium coconut monoglyceride sulfonate 0.75 Sodium carboxymethyl cellulose 1.15 Magnesium aluminum silicates 0.40 Flavoring 0.85 =Disodium salt of ethane l hydroxy 1,1 diphosphonic acid 1.50
1 Prepared in accordance with US. Patent 3,112,247 granted Nov. 26, 1963.
This composition effectively retards calculus formation on dental enamel and when tested in the Continuous Immersion Test described herein no decalcification was noted after seven days exposure.
Toothpaste compositions substantially identical to the composition of Example I are prepared with the trisodium salt of methanediphosphonic acid; the disodium salt of methane-hydroxydiphosphonic acid; ethane-l-amino-l, 1- diphosphonic acid; trisodium salt of methanedichlorodiphosphonic acid; and propane-2, 2-diphosphonic acid, respectively, rather than the disodium salt of ethane-1- hydroxy-l, l-diphosphonic acid, adjusting the pH to 5.9. These compositions substantially retard calculus formation and do not decalcify dental enamel.
Example II A toothpaste was prepared which was substantially identical in composition to the toothpaste of Example I except that 3.0 parts rather than 1.5 parts of disodium dihydrogen ethane-l-hydroxy-l, l-disphosphonate and 30.08 parts rather than 31.58 parts of water was used. This composition was also found to be effective and caused no damage to dental enamel after seven days exposure.
The disodium dihydrogen salt of ethane-l-hydroxy-l, l-diphosphonic acid in the above composition can be replaced by ethane-l-hydroxy-l, l-diphosphonic acid, or any of the potassium, ammonium, or substituted ammonium salts thereof, adjusting the pH of the composition to 7.0, and substantially equivalent results are attained.
Example III Yet another toothpaste was prepared having the following composition:
Parts by weight Water 39.58
When employed in the customary manner, this toothpaste retards the formation of dental calculus and no decalcification of dental enamel was observed after seven days exposure.
Several additional toothpastes are prepared having essentially the same composition as the toothpaste of Example III, but using the tetrasodiurn salt of ethane-1,1,2- triphosphonic acid; the pentasodium salt of propane-1- hydroxy-l,1,3-triphosphonic acid; the pentasodium salt of ethane-l-hydroxy-l,1,2-triphosphonic acid; the pentasodium salt of ethane-2-hydroxy-1,1,2-triphosphonic acid; ethane-Z-naphthyl-l,l-diphosphonic acid; propane-l,2,3-triphosphonic acid, butane-1,2,3,4-tetraphosphonic acid, and hexane-1,2,3,4,5,6-hexaphosphonic acid, respectively, rather than the disodium salt of ethane-l-hydroxy-Ll-diphosphonic acid. The pH of these compositions is adjusted to 7.0. These toothpaste formulations effectively retard calculus formation on dental enamel without decalcifying same.
Example IV A toothpaste composition prepared with 3.0 parts of disodium dihydrogen ethane-l-hydroxy-l, l-diphosph onate and 38.08 parts water, but otherwise substantially identical to the composition of Example III, was prepared. This composition was found to be effective against calculus formation and caused no observable decalcification of dental enamel after seven days exposure.
The disodium dihydrogen salt of ethane-1-hydroxy-1,ldiphosphonic acid employed in this example can be replaced with dipotassium dihydrogen ethane-1-hydroxy-1,1- diphosphonate; diammonium dihydrogen ethane-l-hydroxy-1,1-diphosphonate; or bis(triethanolamrnonium)dihydrogen ethane-l-hydroxy-l,l-diphosphonate, respectively, adjusting the pH of the composition to 8.0. Substantially equivalent results are obtained with these compositions.
Several mouthwash compositions were prepared in accordance with this invention as follows:
Example V 1 Polyoxyethylene (20 moles of ethylene oxide) sorbitan monooleatea nonionic emulsifier supplied by Atlas Powder Company.
2 Disodium salt of ethane-l-hydroxy-l,l-diphosphonic acid.
3 Adjusted to value indicated with sodium hydroxide. 75
When used in the same manner as conventional mouthwash, at least once daily, each of the above compositions materially reduces accumulation of calculus on the surfaces of teeth. No decalcification was observed after seven days exposure of dental enamel to these compositions.
Mouthwash compositions corresponding to Example VII are prepared, substituting the dirnagnesium salt of propane-1,1,3,3-tetraphosphonic acid; the disodium salt of propane-,Z-diphosphonic acid; the tetraammonium salt of ethane-2-carboxy-1,l-diphosphonic acid; nonane-5,5-diphosphonic acid; n-pentane-l,l-diphosphonic acid and ethane-Z-phenyl-l,l-diphosphonic acid, respectively, for the disodium salt of ethane-l-hydroxy-l,l-diphosphonic acid and adjusting the pH to 10.0. These mouthwash compositions retard calculus formation without damaging tooth structure.
Mouthwash compositions corresponding to Example V are prepared, replacing the disodium salt of ethane-l-hydroxy-1,1-diphosphonic acid with pent-4-ene-1-hydroxy- 1,1-diphosphonic acid; octadec-9-enel-hydroxy- 1, l-diphosphonic acid; methane-dichlorodiphosphonic acid; methanedibromodiphosphonic acid; phenylaminoethanediphosphonic, respectively. Each of the resulting mouthwash compositions retard calculus formation without damaging dental enamel.
A number of additional mouthwash compositions are prepared which are similar in formulation to the composition of Example VIII but replacing the disodium salt of ethane-l-hydroxy-l,1-diph0sphonic acid with the disodium salt of hexane-1-hydroxy-2,3,4,5,6-pentaphosphonic acid, the triammonium salt of hexane-1,6-dihydroxy-2,3,4,5 tetraphosphonic acid, the dicalcium salt of pentane- 1,2,3,4,5-pentaphosphonic acid, heptane-l,2,3,4,5,6,7-heptaphosphonic acid and octane-1,2,3,4,5,6,7,8-octa.phosphonic acid, respectively. These compositions are effective in retarding dental calculus formation without damaging dental enamel.
Example IX A prophylaxis paste for use by the dentist for removal of stains and polishing the teeth after mechanical removal of calculus deposits is formulated as follows:
Trisodium salt of ethane-l-hydroxy-1,1-diphosphonic acid pH 8. 0.
When applied to the teeth with a prophylactic rubber cup in the conventional manner, this composition retards the development of new calculus deposits.
The prophylaxis paste set forth above is modified by replacing the trisodium salt of ethane-l-hydroxydiphosphonic acid with N,N-dimethylaminoethanediphosphonic acid; N (2 hydroxyethyl) aminomethanediphosphonic acid; N-acetylaminomethanediphosphonic acid; and aminomethanediphosphonic acid, respectively, with comparable results.
Moreover, dodecane-l,l-diphosphonic acid, the dipotassium salt of 3-phenyl-1,l-diphosphonoprop-Z-ene, or the dimagnesium salt of decane-1,2,3,4,5,6,7,8,9,10-decaphosphonic acid can be used in place of the trisodium salt of ethane-l-hydroxy-1,1-diphosphonic aicd in the composition of Example IX with good results.
Toothpowders and the like can be prepared by conventional methods and containing, in addition to the usual ingredients, an amount of polyhphosphonate within the ranges specified herein, to provide an effective means of retarding calculus formation without damaging the tooth structure.
Those components other than polyphosphonates which were included in the foregoing examples and various mixtures of those components are illustrative of carriers suitable for use in the oral cavity.
In the reference to pH adjustments in the foregoing examples, it is to be understood that a base of a cation corresponding to the salt form of the polyphosphonate employed is used to adjust to higher pH values. In each case in which the polyphosphonate was added in its acid form to the example compositions, the pH was adjusted to the specified higher value with NaOH. Adjustments in pH to more acid levels is accomplished with HCl acid. It will be obvious to those skilled in the art that pH adjustments can be made with any acid or base suitable for use in the oral cavity.
What is claimed is:
1. An oral composition effective in inhibiting the formation of dental calculus without adversely affecting tooth structure, comprising (1) from about .01% to about 10% by weight of a polyphosphonate selected from the group consisting of those of the formulae:
wherein R and R are each hydrogen or CH OI-I; n is an integer of from 3 to 10; R is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, phenyl, naphthyl, phenylethyl, benzyl, halogen, amino, dimethylamino, diethylamino, N-hydroxy-N-ethylamino, acetylamino,
-CH COOH 3H2, PO3H2) 01' CH CH (1 0 1-1 2 R is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl CH COOH, CH PO H or CH CH PO H or a pharmaceutically acceptable salt thereof, and (2) a carrier suitable for use in the oral cavity, the pH of the composition being within the range from about 5.0 to about 11.0.
2. The composition of claim 1 in which the polyphosphonate is ethane-1-hydroxy-1,l-diphosphonic acid or a pharmaceutically acceptable salt thereof.
3. The composition of claim 1 in which the polyphosphonate is methanediphosphonic acid or a pharmaceutical-ly acceptable salt thereof.
4. The composition of claim 1 in which the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt thereof.
5. The composition of claim 1 in which the polyphosphonate is ethane-l-hydroxy-l,1,2-triphosphonic acid or a pharmaceutically acceptable salt thereof.
6. The composition of claim 1 in which the polyphosphonate is methanehydroxydiphosphonic acid or a pharmaceutically acceptable salt thereof.
7. The composition of claim 1 in which the polypho-sphonate is propane-1,1,3,3-tetraphosphonic acid or a pharmaceutically acceptable salt thereof.
8. The composition of claim 1 in which the polyphosphonate is ethane-Z-carboxy-l,l-diphosphonic acid or a pharmaceutically acceptable salt thereof.
9. The composition of claim 1 in which the polyphosphonate is ethane-1,1,2-triphosphonic acid or a pharmaceutically acceptable salt thereof.
10. The composition of claim 1 in which the polyphosphonate is ethane-1-amino-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof.
11. The composition of claim 1 in which the polyphosphonate is methanedichlorodiphosphonic acid or a pharmaceutically acceptable salt thereof.
12. The composition of claim 1 in which the polyphosphonate is nonane-5,S-diphosphonic acid or a pharmaceutically acceptable salt thereof.
13. The composition of claim 1 in which the polyphosphonate is n-pentane-l,l-diphosphonic acid or a pharmecutically acceptable salt thereof.
14. The composition of claim 1 in which the polyphosphonate is methanedibromodiphosphonic acid or a pharmaceutically acceptable salt thereof.
15. The composition of claim 1 in which the polyphosphonate is pronane-l-hydroxy-1,3-triphosphonic acid or a pharmaceutically acceptable salt thereof.
16. The composition of claim 1 in which the polyphosphonate is propane-1,2,3-triphosphor1ic acid or a pharmaoeutically acceptable salt thereof.
17. The composition of claim 1 in which the polyphosphonate is butane-1,2,3,4-tetraphosphonic acid or a pharmaceutically acceptable salt thereof.
18. The composition of claim 1 in which the polyphosphonate is hexane-1,2,3,4,5,6-hexaphosphonic acid or a pharmaceutically acceptable salt thereof.
19. A toothpaste composition comprising (1) from about 0.1% to about 5.0% by weight of a polyphosphonate selected from the group consisting of those of the formulae:
wherein R and R are each hydrogen or CH OH; n is an integer of from 3 to 10; R is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, phenyl, naphthyl, phenylethenyl, benzyl, halogen, amino, dimethylamino, diethylamino, N-hydroxy-N-ethylamino, acety-lamino,
R is hydrogen, lower alkyl, amino, benzyl, halogen, hydroxyl, CH COOH, CH PO H or CH OH PO H or a pharmaceutical-1y acceptable salt thereof, and (2) from about 20% to about 60% by weight of an abrasive material, the pH of said composition being within the range from about 7 to about 10.
20. The composition of claim 19 in which the polyphosphonate is ethane-l-hydroxy-l,l-diphosphonic acid or a pharmaceutically acceptable salt thereof.
References Cited UNITED STATES PATENTS 2,191,199 2/1940 Hall 424-57 3,159,581 12/1964 Diehl 260502.4 3,213,030 10/1965 Diehl 252-152 3,214,454 10/1965 Blaser et al. 260502.4
(Other references on following page) 13 14 UNITED STATES PATENTS Draus et 21].: Dental Progress, vol. 3, N0. 2, pp. 79-81 ,297,5 8 1/1 67 c thfi 1d t 1. 260502.4 JanuarY1963' 3 7 9 Fu c e e a Grossman: J. Oral Surgery, Oral Medicine, and Oral 3,299,123 1/1967 Fltch et a1 260-502.4 3,303,139 2/1967 Blaser et a l 252-180 Paflwlogy, 7, 484-487, May 1954- 3,400,148 9/1968 Quirnby 260502.4 5 3 400 176 9 /19 Quimby 0 502 4 RICHARD L HUFF Pnmary Examiner OTHER REFERENCES US. Cl. X.R.
Dental Abstracts, vol. 12, No. 9, pp. 539-544, Septem- 424-52, 54, 55 be! 1967. 10
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,488 ,419 January 6, 1970 Homer W. McCune et al It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:
Column 2, line 41, "or" should read of Column 6, Table 3, after "phenylaminomethanediphosphonic acid" "2.60 X 10' should read 2.60 x 10' Table 3, after "N-acetylaminomethanediphosphonic acid" "2.,22 X 10 should read 2.22 X 10 Column 7, line 6, "power" should read powerful Column 10, line 9, "propane-,Z-diphosphonic" should read ropane2,2-diphosphonic Column 12, line 8, "methanedichlorodiphosphonic" should read ethanedichlorodiphosphonic line 20, "pronane-lhydroXy-l, S-triphosphonic" should read propane-l-hydroxy-l, 1,3-triphosphonic Signed and sealed this 8th day of September 1970.
(SEAL) Attest:
EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents
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US731312A Expired - Lifetime US3488419A (en) | 1965-12-08 | 1968-05-22 | Oral compositions for calculus retardation |
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US (1) | US3488419A (en) |
CH (1) | CH490855A (en) |
DE (1) | DE1617729B2 (en) |
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FR (1) | FR1514194A (en) |
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SE (1) | SE324635B (en) |
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-
1966
- 1966-11-24 NL NL6616593.A patent/NL149701C/en not_active IP Right Cessation
- 1966-11-25 DE DE1617729A patent/DE1617729B2/en not_active Ceased
- 1966-12-06 IT IT43368/66A patent/IT1008505B/en active
- 1966-12-07 FI FI663245A patent/FI48038C/en active
- 1966-12-07 DK DK633466AA patent/DK114217B/en not_active IP Right Cessation
- 1966-12-07 NO NO165897A patent/NO124095B/no unknown
- 1966-12-07 FR FR86472A patent/FR1514194A/en not_active Expired
- 1966-12-07 SE SE16760/66A patent/SE324635B/xx unknown
- 1966-12-07 CH CH1747466A patent/CH490855A/en not_active IP Right Cessation
- 1966-12-08 GB GB55029/66A patent/GB1110987A/en not_active Expired
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1968
- 1968-05-22 US US731312A patent/US3488419A/en not_active Expired - Lifetime
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US3678154A (en) * | 1968-07-01 | 1972-07-18 | Procter & Gamble | Oral compositions for calculus retardation |
US3979385A (en) * | 1969-11-19 | 1976-09-07 | Henkel & Cie G.M.B.H. | 1-Aminoalkane-1,1-diphosphonic acids and their salts |
US3683080A (en) * | 1970-08-28 | 1972-08-08 | Procter & Gamble | Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue |
FR2124283A1 (en) * | 1971-02-01 | 1972-09-22 | Henkel & Cie Gmbh | |
US3934002A (en) * | 1972-06-30 | 1976-01-20 | The Procter & Gamble Company | Oral compositions for plaque, caries and calculus retardation with reduced staining tendencies |
US4025616A (en) * | 1973-03-06 | 1977-05-24 | The Procter & Gamble Company | Oral compositions for plaque, caries and calculus retardation with reduced staining tendencies |
US4083972A (en) * | 1973-06-19 | 1978-04-11 | The Procter & Gamble Company | Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue |
US4108962A (en) * | 1974-11-30 | 1978-08-22 | Henkel Kommanditgesellschaft Auf Aktien | Process of stabilization of anhydrous dibasic calcium phosphate against fluorine ions with 3-amino-1-hydroxypropane-1,1-diphosphonic acid |
US4117086A (en) * | 1974-11-30 | 1978-09-26 | Henkel Kommanditgesellschaft Auf Aktien | Process of stabilization of dibasic calcium phosphate dihydrate against hydrolysis with 3-amino-1-hydroxypropane-1,1-diphosphonic acid |
US4122151A (en) * | 1974-11-30 | 1978-10-24 | Henkel Kommanditgesellschaft Auf Aktien | Process of stabilization of dibasic calcium phosphate dihydrate against hydrolysis with cyclic aminophosphonic acids |
US4130630A (en) * | 1974-11-30 | 1978-12-19 | Henkel Kommanditgesellschaft Auf Aktien (Henkel Kgaa) | Process of stabilization of anhydrous dibasic calcium phosphate against fluorine ions with cyclic aminophosphonic acids |
US4042679A (en) * | 1975-11-07 | 1977-08-16 | Colgate-Palmolive Company | Antibacterial oral composition |
US4820507A (en) * | 1983-12-17 | 1989-04-11 | Henkel Kommanditgesellschaft Auf Aktien | Oral and dental hygiene preparations |
US4569838A (en) * | 1983-12-23 | 1986-02-11 | Colgate-Palmolive Company | Dentifrice |
AT388292B (en) * | 1983-12-23 | 1989-05-26 | Colgate Palmolive Co | TOOTHPASTE |
US4726943A (en) * | 1984-10-25 | 1988-02-23 | Henkel Kommanditgesellschaft Auf Aktien | Anti-caries composition |
US4575456A (en) * | 1984-11-30 | 1986-03-11 | Colgate-Palmolive Company | Gel dentifrice of desirable consistency |
EP0236827A2 (en) * | 1986-03-07 | 1987-09-16 | Blendax GmbH | Toothpaste |
EP0236827A3 (en) * | 1986-03-07 | 1988-04-06 | Blendax-Werke R. Schneider Gmbh & Co. | Toothpaste |
US4908138A (en) * | 1987-07-25 | 1990-03-13 | Henkel Kommanditgesellschaft Auf Aktien | Hydroxyacetonitrile diphosphonic acid, a process for its production, and its use |
US4880575A (en) * | 1987-07-25 | 1989-11-14 | Henkel Kommanditgesellschaft Auf Aktien | Olefinic diphosphonic acids, a process for their production, their use as thresholders and complexing compositions containing them |
US5324505A (en) * | 1988-12-12 | 1994-06-28 | Henkel Kommanditgeselschaft Auf Aktien | Striped, multicolored toothpaste and dispenser therefor |
US5000973A (en) * | 1989-05-30 | 1991-03-19 | Nabisco Brands, Inc. | Nutritionally-balanced canine biscuits containing an inorganic pyrophosphate |
US5000943A (en) * | 1989-05-30 | 1991-03-19 | Nabisco Brands, Inc. | Canine biscuits containing an inorganic pyrophosphate |
US5000940A (en) * | 1989-05-30 | 1991-03-19 | Nabisco Brands, Inc. | Devices, compositions and the like having or containing an inorganic pyrophosphate |
US5011679A (en) * | 1989-05-30 | 1991-04-30 | Nabisco Brands, Inc. | Raw hide having a coating containing an inorganic pyrophosphate |
US5015485A (en) * | 1989-05-30 | 1991-05-14 | Nabisco Brands, Inc. | Dog biscuits having a coating containing an inorganic pyrophosphate |
US5047231A (en) * | 1989-05-30 | 1991-09-10 | Nabisco Brands, Inc. | Raw hide containing an inorganic pyrophosphate |
US5094870A (en) * | 1989-05-30 | 1992-03-10 | Nabisco Brands, Inc. | Canine biscuits containing an inorganic pyrophosphate |
US5114704A (en) * | 1989-05-30 | 1992-05-19 | Nabisco Brands, Inc. | Raw hide having a coating containing an inorganic pyrophosphate |
US5279814A (en) * | 1990-03-09 | 1994-01-18 | Henkel Kommanditgesellschaft Auf Aktien | Oral-hygiene/dentifrice preparations which protect dental enamel |
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US5318772A (en) * | 1991-12-10 | 1994-06-07 | The Dow Chemical Company | Oral compositions for inhibiting calculus formation |
US5320829A (en) * | 1991-12-10 | 1994-06-14 | The Dow Chemical Company | Oral compositions for inhibiting plaque formation |
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Also Published As
Publication number | Publication date |
---|---|
NL149701B (en) | 1976-06-15 |
FI48038B (en) | 1974-02-28 |
FI48038C (en) | 1974-06-10 |
DE1617729A1 (en) | 1971-04-08 |
NL149701C (en) | 1981-05-15 |
GB1110987A (en) | 1968-04-24 |
CH490855A (en) | 1970-05-31 |
DK114217B (en) | 1969-06-09 |
SE324635B (en) | 1970-06-08 |
DE1617729B2 (en) | 1973-09-13 |
IT1008505B (en) | 1976-11-30 |
FR1514194A (en) | 1968-02-23 |
NO124095B (en) | 1972-03-06 |
NL6616593A (en) | 1967-06-09 |
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